Glioblastomas are considered to be one of the most difficult human malignancies to treat.
Clinical and experimental studies have shown infiltration of malignant glioma tissue with brain resident macrophages (microglia), peripheral monocyte/macrophages and myeloid-derived suppressive cells. Intratumoral density of those cells increases during glioma progression and correlates with malignancy and ablation of microglia in organotypic brain slice cultures and animal glioma models have demonstrated its significant role in supporting glioma invasion (Gabrusiewicz K. et al., PLoS One; 6(8):e23902, 2011).
It is suggested that macrophages are attracted by tumor-released molecules and instead of initiating anti-tumor responses, those cells support invasion, angiogenesis, extracellular matrix remodeling and immunosuppression in different types of tumors (Gabrusiewicz K. et al., ibid).
Osteopontin (OPN) is an integrin binding ligand shown to bind to several integrin receptors including α4β1, α9β1, and α9β4 expressed by leukocytes. OPN is expressed in a range of immune cells, including macrophages, neutrophils, dendritic cells, and T and B cells. OPN is reported to act as an immune modulator. It has chemotactic properties, which promote cell recruitment to inflammatory sites. It also functions as an adhesion protein, involved in cell attachment and wound healing. In addition, OPN mediates cell activation and cytokine production, as well as promoting cell survival by regulating apoptosis.
The role of OPN in activation of macrophages has also been implicated in a cancer study, where researchers discovered that OPN-producing tumors were able to induce macrophage activation compared to OPN-deficient tumors (Crawford H C, et al. 1998 Cancer Res. 58 (22): 5206-15).
Lactadherin, also known as milk fat globule-epidermal growth factor 8 (EGF-8), is a glycoprotein secreted by macrophages. Lactadherin binds to apoptotic cells, activated platelets, and phosphatidylserine-expressing red blood cells and anchors them to macrophage integrins via its RGD sequence.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a protein secreted by macrophages, T cells, mast cells, NK cells, endothelial cells and fibroblasts. GM-CSF is a cytokine that functions as a white blood cell growth factor. Thus, it is part of the immune/inflammatory cascade, by which activation of a small number of macrophages can rapidly lead to an increase in their numbers, a process crucial for fighting infection.
There is an unmet need for identifying inhibitors that can inhibit the pro-tumor activity of macrophages in tumors such as gliomas.